Exposure to
organophosphate (OP)
nerve agents, such as
sarin, may lead to uncontrolled
seizures and irreversible
brain injury and neuropathology. In rat studies, a median lethal dose of
sarin leads to approximately half of the animals developing
seizures. Whereas previous studies analyzed transcriptomic effects associated with seizing
sarin-exposed rats, our study focused on the cohort of
sarin-exposed rats that did not develop
seizures. We analyzed the genomic changes occurring in
sarin-exposed, non-seizing rats and compared differentially expressed genes and pathway activation to those of seizing rats. At the earliest time point (0.25 h) and in multiple
sarin-sensitive brain regions, defense response genes were commonly expressed in both groups of animals as compared to the control groups. All
sarin-exposed animals activated the MAPK signaling pathway, but only the seizing rats activated the apoptotic-associated JNK and
p38 MAPK signaling sub-pathway. A unique phenotype of the non-seizing rats was the altered expression levels of genes that generally suppress
inflammation or apoptosis. Importantly, the early transcriptional response for
inflammation- and apoptosis-related genes in the thalamus showed opposite trends, with significantly down-regulated genes being up-regulated, and vice versa, between the seizing and non-seizing rats. These observations lend support to the hypothesis that regulation of anti-inflammatory genes might be part of an active and sufficient response in the non-seizing group to protect against the onset of
seizures. As such, stimulating or activating these responses via pretreatment strategies could boost resilience against
nerve agent exposures.